Autoimmune diseases are chronic disorders affecting approximately 5-8% of the human population, mostly women. Although genetic predisposition is clearly important, the relatively low concordance rate of autoimmunity in monozygotic twins (<40%) suggests the critical contribution of environmental factors, particularly infectious agents. Indeed, several autoimmune diseases have been tentatively linked to various viral infections. However, because an autoimmunity-provoking infection may occur long before disease onset and the virus may be cleared by the time symptoms appear, direct associations between specific viruses and autoimmune entities have been difficult to establish. Thus, an alternative approach to investigate the role of virus infection in autoimmunity may be by conducting such studies using well-characterized virus variants and mouse strains that display various degrees of genetic predisposition to autoimmunity. In preliminary studies, we have shown that persistent infection with lymphocytic choriomeningitis virus (LCMV) causes severe acceleration of lupus disease in genetically predisposed mice. Here we will use this model to define: 1) the role of virus type and time of infection; 2) mechanistic aspects of virus-mediated disease acceleration focusing on synergistic effects in innate immune stimulatory pathways; and 3) potential therapeutic approaches designed on the basis of specific pathogenic mechanisms.